Human newborns are still at risk for brain damaged and hearing loss from bilirubin toxicity despite advances in the care and treatment of hyperbilirubinemia. The spectrum of bilirubin encephalopathy today ranges from classic kernicterus in premature, low-birth-weight infants, to more subtle conditions or the isolated sequelae of hearing loss and cognitive dysfunction. The incidence of impairment due to bilirubin toxicity, especially in the subtle or isolated conditions, is largely unknown because it is difficult to relate abnormalities that appear later in life to transient biochemical abnormalities that occur in the newborn period. Furthermore, the pathogenesis, localization of sites of auditory nervous system dysfunction, and the determinants of vulnerability and reversibility are still only partially understood despite decades of study. In a continuation of our successful use of brainstem auditory evoked potentials (BAEPs) in the Gunn rat model of bilirubin encephalopathy, we will combine noninvasive neurophysiological recordings with quantitative neuroanatomical studies, biochemical measurements, and immunohistochemistry to provide a cohesive synthesis of the localization, reversibility and pathogenesis of dysfunction due to bilirubin toxicity and its interaction with developmental processes. Electrophysiologic findings that occur soon after acute exposure to bilirubin toxicity will be compared to anatomic and biochemical measures. Interventions aimed at reversing acute bilirubin toxicity will be used to explore the time constraints of reversibility of the pathological process. Studies at different ages early in development will examine the vulnerability of different areas of the immature auditory and central nervous systems to bilirubin toxicity. We will continue our efforts to localize the specific site(s) of bilirubin-induced auditory nervous system dysfunction utilizing BAEPs, otoacoustic emissions, binaural interaction evoked potentials, and later-latency evoked potentials to assess damage to the cochlea and the central auditory nervous system, and verify our electrophysiologic results with anatomic and biochemical experiments. The resulting multidisciplinary approach is expected to provide new insights into the localization, pathogenesis, and reversibility of this disorder, and its effects on the auditory system. Understanding the complex relationships between electrophysiological, anatomical and biochemical processes in animal models of bilirubin encephalopathy should lead to improved noninvasive procedures for predicting, preventing, and treating the neurological and audiological sequelae of bilirubin toxicity in human newborns.